The thiazolidinedione (TZD) drugs, including rosiglitazone (Avandia) and pioglitazone (Actos), are insulin sensitizers that are widely used to treat type 2 diabetes mellitus. They mediate their therapeutic effects by activating peroxisome proliferatoractivated receptor &#947;(PPAR&#947;), a nuclear receptor that is highly expressed in adipose tissue. The clinical use of TZDs is limited by their side effects, which include weight gain, edema, and increased risk of bone fracture and heart failure. Despite their well characterized antidiabetic effects, the molecular underpinnings of TZD action are not completely understood, which has hampered the development of new generations of safer insulin-sensitizing drugs. We now show that the insulin-sensitizing actions of TZDs in diet-induced obese (DIO) mice require fibroblast growth factor 21 (FGF21), a hormone that is induced by TZDs in adipose tissue. Previous work has shown that pharmacologic administration of FGF21 to insulin-resistant rodents or monkeys causes profound insulin sensitization without the side effects caused by TZDs. Based on these data, we hypothesize that TZDs mediate their insulin-sensitizing actions in part by inducing FGF21 in adipose tissue. The overarching goal of this proposal is to understand the relationship between TZDs, FGF21, PPAR&#947;and insulin sensitization. The three specific aims are: (1) to determine the contribution of FGF21 to the antidiabetic actions of TZDs; (2) to determine whether FGF21 and its receptor constituents, FGFR1 and &#946;klotho, are required in adipose tissue and/or liver for the antidiabetic actions of TZDs;and (3) to examine the molecular relationship between FGF21 and PPAR&#947;activity in white adipose tissue. As part of these studies, we will also examine the contribution of FGF21 to the well-established side effects of TZDs. These studies will provide important insights into the mechanisms whereby TZDs regulate insulin sensitivity and help guide the development of future drugs to treat type 2 diabetes.